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A novel small-molecule MRCK inhibitor blocks cancer cell invasion

DOI: 10.1186/s12964-014-0054-x DOI Help
PMID: 25288205 PMID Help

Authors: Mathieu Unbekandt (Cancer Research UK Beatson Institute) , Daniel R. Croft (Cancer Research UK Beatson Institute) , Diane Crighton (Cancer Research UK Beatson Institute) , Mokdad Mezna (Cancer Research UK Beatson Institute) , Duncan Mcarthur (Cancer Research UK Beatson Institute) , Patricia Mcconnell (Cancer Research UK Beatson Institute) , Alexander W. Schüttelkopf (Cancer Research UK Beatson Institute) , Simone Belshaw (Cancer Research UK Beatson Institute) , Andrew Pannifer (Beatson Institute for Cancer Research) , Mairi Sime (Cancer Research UK Beatson Institute) , Justin Bower (Cancer Research UK Beatson Institute) , Martin Drysdale (Cancer Research UK Beatson Institute) , Michael F. Olson (Cancer Resarch UK Beatson Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Communication And Signaling , VOL 12 , PAGES 3583-3590

State: Published (Approved)
Published: October 2014
Diamond Proposal Number(s): 8659

Open Access Open Access

Abstract: Background: The myotonic dystrophy kinase-related CDC42-binding kinases MRCKβ and MRCKβ regulate actin-myosin contractility and have been implicated in cancer metastasis. Along with the related ROCK1 and ROCK2 kinases, the MRCK proteins initiate signalling events that lead to contractile force generation which powers cancer cell motility and invasion. A potential strategy for cancer therapy is to reduce metastasis by blocking MRCK activity, either alone or in combination with ROCK inhibition. However, to date no potent small molecule inhibitors have been developed with selectivity towards MRCK. Results: Screening a kinase-focused small molecule chemical library resulted in the identification of compounds with inhibitory activity towards MRCK. Medicinal chemistry combined with in vitro enzyme profiling led to the discovery of 4-chloro-1-(4-piperidyl)-N-[5-(2-pyridyl)-1H-pyrazol-4-yl]pyrazole-3-carboxamide (BDP00005290; abbreviated as BDP5290) as a potent MRCK inhibitor. X-ray crystallography of the MRCKβ kinase domain in complex with BDP5290 revealed how this ligand interacts with the nucleotide binding pocket. BDP5290 demonstrated marked selectivity for MRCKβ over ROCK1 or ROCK2 for inhibition of myosin II light chain (MLC) phosphorylation in cells. While BDP5290 was able to block MLC phosphorylation at both cytoplasmic actin stress fibres and peripheral cortical actin bundles, the ROCK selective inhibitor Y27632 primarily reduced MLC phosphorylation on stress fibres. BDP5290 was also more effective at reducing MDA-MB-231 breast cancer cell invasion through Matrigel than Y27632. Finally, the ability of human SCC12 squamous cell carcinoma cells to invade a three-dimensional collagen matrix was strongly inhibited by 2 μM BDP5290 but not the identical concentration of Y27632, despite equivalent inhibition of MLC phosphorylation. Conclusions: BDP5290 is a potent MRCK inhibitor with activity in cells, resulting in reduced MLC phosphorylation, cell motility and tumour cell invasion. The discovery of this compound will enable further investigations into the biological activities of MRCK proteins and their contributions to cancer progression.

Journal Keywords: Chelerythrine; SCC12 Cell; DMSO Vehicle; Rock Kinase; Essen BioScience

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 26/03/2015 15:16


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)